The present invention relates to the use of a neutral or cationic polymer, combined, before sterilization, with a semi-permeable membrane based on polyacrylonitrile bearing fixed negative charges, which is fitted in apparatus for the treatment of blood or plasma by extra-corporal circulation, to prevent activation of the contact phase of blood or plasma.
The subject of the present invention is also apparatus for the treatment of blood or plasma by extra-corporal circulation, which prevents activation of the contact phase of blood or plasma, as well as processes for manufacturing this apparatus.
Apparatus for the treatment of blood or plasma by extra-corporal circulation is used in various medical or paramedical applications, such as: treatment of renal insufficiency by dialysis or haemofiltration, plasmapheresis and apheresis for therapeutic and non-therapeutic purposes, oxygenation of the blood, immunopurification, etc.
Activation of the contact phase of blood or plasma appears to take place in particular when apparatus for the treatment of blood or plasma by extra-corporal circulation is used, which includes a negatively-charged semi-permeable membrane, without, in the absence of disruptive factors, the patients experiencing the slightest discomfort. Activation of the contact phase is described as a biological phenomenon which takes place in the case of patients undergoing blood (or plasma) treatment by extra-corporal circulation, when the blood comes into contact with the negatively charged surface of the membrane of certain apparatus for blood and plasma treatment. This biological phenomenon results in the generation of active substances, kallicrein and factor XIIa from inactive substances, prekallicrein and factor XII, kallicrein having a catalytic effect on the production of factor XIIa, and vice versa. In addition, kallicrein is the cause of the transformation of a plasma protein, high molecular weight kininogen, into a peptide substance, bradykinin.
When activation of the contact phase takes place simultaneously with certain disruptive factors such as, for example:
the presence, in the blood to be treated, of medicinal products for combating arterial hyper-tension by inhibition of the natural mechanism of vasoconstriction, these products being referred to generically as conversion enzyme inhibitors, or CEIs. These CEIs are also used for other therapeutic applications, in particular for treating certain forms of cardiac insufficiency,
dilution of the blood entering the apparatus filled with saline solution and concomitant lowering of the blood pH,
activation of the contact phase appears to be the cause of adverse reactions called anaphylactoid.
These anaphylactoid reactions develop, a few minutes after the start of the treatment, by various symptoms, including a generalized sensation of hotness, swelling of the fingers, the lips or the tongue, gasping for breath, nausea and laryngeal oedema.
Anaphylactoid reactions have been observed in particular in the case of renal insufficiency patients treated by haemodialysis, haemofiltration or haemodiafiltration with the aid of apparatus for the treatment of the blood in the form of a dialyser or exchanger containing a membrane.
Anaphylactoid reactions have been observed with exchangers containing membranes of various chemical compositions, sometimes during a first use, sometimes after several uses when the exchangers, rather than being discarded after a single use, are reused several times and recycled after each use. As examples of exchangers for which a first use has been accompanied by an adverse reaction, mention may be made of dialysers containing a membrane based on polymethyl methacrylate and on poly-acrylonitrile. Reactions associated with the reuse of dialysers containing a membrane based on cellulose acetate and on polysulphone have also been well documented (see the article entitled xe2x80x9cAnaphylactoid reactions associated with reuse of hollow-fibber haemo-dialysers and ACE inhibitorsxe2x80x9d in xe2x80x9cKidney Internationalxe2x80x9d, vol. 42 (1992), pp. 1232-1237).
Anaphylactoid reactions are ascribed to an excessive concentration of bradykinin in the blood or in the plasma.
In order to avoid the generation of bradykinin at a concentration above 4000 pg/ml, European patent No. 0,561,379 recommends placing the blood or the plasma in contact only with semi-permeable membranes which have a limited surface charge density, i.e. an overall surface electrical charge of greater than or equal to xe2x88x9230 xcexceg/g of membrane, this electrical charge being measured by a method chosen from the group consisting of the dye adsorption method, the salt cleavage method, the method of titration to neutralization and the iodine method.
However, from the description of the invention claimed in European patent No. 0,561,379, in particular from the measuring methods proposed, it emerges that the surface electrical charge in fact corresponds to the overall ionic capacity of the semi-permeable membranes. Consequently, this European patent relates only to semi-permeable membranes with an overall ionic capacity of greater than or equal to xe2x88x9230 xcexceq/g of membrane, but not to semi-permeable membranes with an overall ionic capacity of very much less than xe2x88x9230 xcexceq/g of membrane, such as, for example, the membrane manufactured by the company Hospal from a copolymer of acrylonitrile and of sodium methallyl sulphonate, which is known under the trade name AN69.
Now, it is desirable not to modify the ionic capacity of membranes since this capacity gives rise to the adsorption and/or transfer of: certain proteins such as xcex22-microglobulin, inflammation mediators and complement factors; lipids. This is particularly true for membranes with a homogeneous, symmetrical structure.
Moreover, the Applicant has observed, that on several examples, that a membrane which has an overall ionic capacity of greater than xe2x88x9230 xcexceq/g of membrane can lead to activation of the contact phase, whereas, conversely, a membrane with an overall ionic capacity which is markedly less than xe2x88x9230 xcexceq/g of membrane cannot lead to activation of the contact phase.
Given the preceding observations, at the present time, a solution which is satisfactory, in both medical and economic terms, for preventing activation of the contact phase of blood or plasma which comes into contact with a negatively-charged semi-permeable membrane does not appear to be known.
One aim of the invention is thus to solve the abovementioned problem with apparatus for the treatment of blood or plasma by extra-corporal circulation, comprising a semi-permeable membrane based on polyacrylonitrile bearing fixed negative charges, which possesses two characteristics that have hitherto been considered antinomic, i.e.:
a negative overall ionic capacity, corresponding to an excess of negative charges, which simultaneously participates in the biocompatibility of the membrane and is a factor for triggering activation of the contact phase, and
a capacity not to produce activation of the contact phase under normal conditions for a first use.
Another aim of the invention is to solve the above-mentioned problem with sterilized apparatus for the treatment of blood or plasma by extra-corporal circulation, which has a capacity not to produce activation of the contact phase under normal conditions for a first use and which is stable in storage. Lastly, another aim of the invention is sterilized apparatus for the treatment of blood or plasma by extra-corporal circulation, which has a capacity not to produce activation of the contact phase under normal conditions for a first use and which is ready to use, i.e. which does not require any special manipulation on the part of the user of the apparatus, such as a special manipulation for the purposes of preventing the adverse effects of activation of the contact phase.
To this effect, the invention proposes the use of a neutral or cationic polymer for preventing activation of the contact phase of blood or plasma which comes into contact with a semi-permeable membrane based on poly-acrylonitrile bearing fixed negative charges, which is fitted in apparatus for the treatment of blood or plasma, by extra-corporal circulation, according to which:
(1) the neutral or cationic polymer is combined with this semi-permeable membrane, before or after formation of the membrane, and before sterilization of the membrane;
(2) the overall ionic capacity of the semi-permeable membrane, based on polyacrylonitrile bearing fixed negative charges and containing a neutral or cationic polymer, is negative;
(3) the overall ionic capacity of the semi-permeable membrane, based on polyacrylonitrile bearing fixed negative charges and containing a neutral or cationic polymer, is, as an absolute value, not more than 10% less than the overall ionic capacity of the same semi-permeable membrane which does not contain a neutral or cationic polymer; preferably, it is, as an absolute value, not more than 1% less than the overall ionic capacity of the same semi-permeable membrane which does not contain a neutral or cationic polymer;
(4) the semi-permeable membrane containing a neutral or cationic polymer complies, before sterilization, with one or other of the following two electrical characteristics:
the electrokinetic index xe2x80x9cIxe2x80x9d which is equal to Log10 (|Z|/R), i.e. to the logarithm, in base 10, of the ratio |Z|/R of the Zeta potential xe2x80x9cZxe2x80x9d, as an absolute value, expressed in microvolts (or xcexcV), of the surface of the membrane intended to come into contact with the blood or plasma, to the electrical resistivity xe2x80x9cRxe2x80x9d of the membrane, expressed in ohm.centimetres (or xcexa9xc2x7cm), is less than or equal to 0.8, or
the Zeta potential xe2x80x9cZxe2x80x9d is positive and is between 0 and +15 mV (limits not included).
Preferably, the electrokinetic index xe2x80x9cIxe2x80x9d is less than or equal to 0.7 and better still less than or equal to 0.6.
Preferably, when the Zeta potential is positive, it is strictly less than 15 mV and greater than or equal to 1 mV. Better still, the Zeta potential is greater than or equal to 6 mV and strictly less than 15 mV.
In order to obtain the electrokinetic index xe2x80x9cIxe2x80x9d:
the Zeta potential xe2x80x9cZxe2x80x9d is calculated by measuring the potential xe2x80x9cExe2x80x9d, expressed in volts, created by the flow of an electrolyte (10xe2x88x922M NaCl) , for example inside a bundle of hollow fibers. This potential xe2x80x9cExe2x80x9d, measured between two Ag/AgCl electrodes connected to a high-impedance volt-meter (Keithley 617), is linked to the Zeta potential xe2x80x9cZxe2x80x9d, expressed in volts, by the Helmholtz-Smoluchowski law:   Z  =            4      ⁢              xe2x80x83            ⁢      π      ⁢              xe2x80x83            ⁢      v      ⁢              xe2x80x83            ⁢      λ      ⁢              xe2x80x83            ⁢      E              ϵ      P      
where:
P is the hydrostatic pressure giving rise to the flow of the electrolyte, in millimetres of mercury (mmHg) (the ratio E/p is referred to as the flow potential),
v is the dynamic viscosity of the electrolyte, in Pascals,
xcex is the actual electrical conductivity of the system in equilibrium with the electrolyte (obtained by measuring the resistance with 10xe2x88x922M NaCl) and is expressed in Siemens/m,
∈ is the dielectric constant of the electrolyte, or the permittivity.
and the electrical resistivity xe2x80x9cRxe2x80x9d, expressed in xcexa9xc2x7cm, is deduced by measuring the electrical resistance of the semi-permeable membrane in equilibrium with an electrolyte (5xc3x9710xe2x88x925M NaCl), using a Wheatstone bridge which functions with an alternating current (Wawetek generator, model 19, frequency 10 Hz).
The experimental determination of the electrical characteristics of the semi-permeable membrane containing a neutral or cationic polymer must be carried out before sterilizing the membrane in the case of a sterilization by irradiation. Otherwise, the obtained values are nonsensical and can not be directly in correlation with the amount of neutral or cationic polymer to be used. In the other, less energetic modes of sterilization, such as sterilization with ethylene oxide, this experimental determination can be carried out before or after sterilization.
In the context of the invention, it is estimated that activation of the contact phase is effective as soon as the maximum concentration of kallicreins (KK) produced during the first 10 minutes of contact with blood or plasma exceeds 10 units of kallicreins (KK) per litre of blood or plasma (10 UKK/l), taking into account the sensitivity of the chromogenic test used.
The term xe2x80x9csemi-permeable membranexe2x80x9d is intended to refer to a flat membrane or a bundle of hollow fibers. Consequently, the apparatus for the treatment of blood or plasma by extra-corporal circulation generally comprises two compartments separated by the semi-permeable membrane.
The expression xe2x80x9csemi-permeable membrane based on polyacrylonitrile bearing fixed negative chargesxe2x80x9d is intended to refer to a semi-permeable membrane consisting of polyacrylonitrile to which anionic functional groups are attached via covalent bonds, this negatively-charged polyacrylonitrile not being water-soluble.
The expression xe2x80x9cneutral or cationic polymer combined (or incorporated) with the semi-permeable membranexe2x80x9d is intended to mean that this polymer is introduced:
either into the mass of the negatively-charged polyacrylonitrile (this process is more particularly suitable for the neutral polymer),
or to the surface of the semi-permeable membrane, for example by placing the membrane in contact with a solution containing the polymer (this process is more particularly suitable for the cationic polymer) or by spraying with a solution containing the polymer.
In addition, the operating conditions for carrying out this combination (or incorporation) are designed to promote the presence of at least some of the neutral or cationic polymer at the surface of the semi-permeable membrane (for example by promoted migration of the neutral polymer or ionic bonding of the cationic polymer).
The term xe2x80x9cswollen polymerxe2x80x9d is intended to refer here to the membrane hydrated to the content corresponding to the clinical use.
Surprisingly, it has been found that it is possible to prevent activation of the contact phase, which can occur fleetingly during the use of apparatus for the treatment of blood or plasma by extra-corporal circulation, by means of a semi-permeable membrane based on polyacrylonitrile bearing fixed negative charges, by modifying the electrical characteristics of the membrane, so that one or other of the following two conditions are satisfied, before sterilization:
the electrokinetic index xe2x80x9cIxe2x80x9d, which is equal to Log10 |Z|/R, is less than or equal to 0.8, or
the Zeta potential xe2x80x9cZxe2x80x9d is positive and ranges between 0 and +15 mV (limits not included), while at the same time substantially maintaining the overall ionic capacity of the membrane, the modification of these electrical characteristics being obtained by combining this membrane with a suitable amount of neutral or cationic polymer, this combination being carried out:
firstly, before sterilization,
secondly, before or after formation of this membrane.
The prevention of activation of the contact phase has in particular been obtained with semi-permeable membranes based on highly negatively-charged polyacrylonitrile, reaching overall ionic capacities of less than or equal to xe2x88x92100 xcexceq/g of swollen polymer.
Surprisingly also, sterilization of the apparatus has no influence on its capacity to prevent activation of the contact phase.
Under the normal conditions of use of the apparatus according to the invention, the known qualities of the semi-permeable membrane are kept intact when this same membrane contains a neutral or cationic polymer: for example, for a haemodialysis/haemofiltration membrane, the haemocompatibility, the performance levels in terms of diffusive and convective transfers, the capacity for adsorbing undesirable substances, etc, are kept intact.
In addition, interestingly, it has not been noticed adsorption of the anticoagulant agents, such as heparin, in a semi-permeable membrane, based on polyacrylonitrile bearing fixed negative charge, modified according to the present invention, in the case the sterilization is carried out by irradiation.
According to the invention, the semi-permeable membrane based on negatively-charged polyacrylonitrile, before combination with a neutral or cationic polymer, has a density of electronegative surface charges corresponding to excesses of negative charges which can be detected, in particular by the electrokinetic potential measurements (Zeta potential). The neutral or cationic polymer makes it possible to mask, at least partly, the electronegative charges present at the surface of the membrane. In the case of a cationic polymer, the negative charges on the membrane are masked in particular by ionic bonding.
Preferably, the neutral polymer is water-soluble at room temperature (about 20xc2x0 C.).
Preferably, the cationic polymer is water-soluble at room temperature (about 20xc2x0 C). However, a cationic polymer which is soluble in an organic solvent, such as alcohols, may be suitable for the invention.
The neutral or cationic polymer must be able to withstand energetic sterilization, such as gamma irradiation. In other words, at least some of the polymer must remain intact and be able to mask, in the desired manner, some of the electronegative surface charges of the membrane. Moreover, the polymer fixed to the membrane and irradiated must not become toxic.
The weight-average molecular mass of the polymer is at least equal to 10,000 daltons.
Advantageously, the weight-average molecular mass of the neutral polymer is greater than 40,000 daltons, preferably greater than 100,000 daltons, and the average molecular mass of the cationic polymer is greater than 25,000 daltons, preferably greater than 100,000 daltons. These molecular masses are measured by a light-scattering method. As polymers which are suitable for carrying out the present invention, mention may be made, as neutral polymers, of polyvinylpyrrolidones (PVP) and polyethylene glycols (PEG) of different molecular masses; as cationic polymers, mention may be made of hydrophilic cationic polymers capable of being adsorbed onto a semi-permeable membrane which has an electronegative surface charge density, such as polyamines, for example polyethyleneimines (PEI), diethylaminoethyl dextrans or DEAE dextrans, and polymers and copolymers containing one or several quaternary ammonium groups.
According to a preferred embodiment of the invention, the polymer is cationic. Preferably also, it is chosen from polyethyleneimines (PEI).
The amount of neutral or cationic polymer to be combined with the membrane depends on the electrical characteristics (Z, R, I) targeted and is variable depending on the chemical nature of the polymer, but does not exceed 10% of the mass of polyacrylonitrile. This amount is generally not more than 2% of the mass of polyacrylonitrile constituting the membrane in the case of the neutral polymer.
The amount of cationic polymer to be combined with the membrane is preferably between about 1 and about 10 mg per m2 of membrane intended to be in contact with blood or plasma (this amount is very much less than 1% of the mass of polyacrylonitrile constituting the membrane).
The invention is particularly suitable for semi-permeable membranes based on polyacrylonitrile bearing fixed negative charges which give it a high absolute value of overall ionic capacity, even after incorporation of the neutral or cationic polymer.
Thus, the invention is particularly suitable for semi-permeable membranes, based on polyacrylonitrile bearing fixed negative charges and containing a neutral or cationic polymer, which have an overall ionic capacity of less than xe2x88x9230 xcexceq per g of swollen polymer (i.e. the membrane), preferably less than xe2x88x9250 xcexceq per g of swollen polymer, as measured by the standard ion-exchange method: by way of reference, the electronegative polymer used to prepare the membrane made of AN69 has an overall ionic capacity or density of negative charges equal to about xe2x88x92180 xcexceq per g of swollen polymer.
Advantageously, the semi-permeable membrane is a flat membrane or a bundle of hollow fibers based on an acrylonitrile homopolymer or copolymer and combined with a neutral or cationic polymer. As examples of acrylonitrile copolymers, mention may be made of:
(1) a copolymer of acrylonitrile and of at least one anionic or anionizable monomer containing, where appropriate, units derived from at least one other monomer containing olefinic unsaturation which is capable of being copolymerized with acrylonitrile, or
(2) a copolymer of acrylonitrile and of at least one nonionic and non-ionizable monomer containing, where appropriate, units derived from at least one other monomer containing olefinic unsaturation which is capable of being copolymerized with acrylonitrile.
Some of these polyacrylonitriles, as well as the various monomers which can be selected as starting materials, and their manufacture, are described more fully in U.S. Pat. No. 4,545,910 reissued under No. Re.34239.
Among these polyacrylonitriles, those with which the invention is particularly suitable are defined under (1) above. In particular, the invention is particularly suitable for those for which the anionic or anionizable comonomer is olefinically unsaturated and bears anionic groups chosen from sulphonate, carboxyl, phosphate, phosphonate and sulphate groups, and, even more particularly, when this comonomer is sodium methallyl sulphonate.
The precise nature of the counterion for the anionic groups is not essential for the correct functioning of the invention.
A subject of the invention is also processes for manufacturing apparatus for the treatment of blood or plasma by extra-corporal circulation, for preventing activation of the contact phase and comprising a semi-permeable membrane in the form of a flat membrane or a bundle of hollow fibers, based on polyacrylonitrile bearing fixed negative charges and combined with a neutral or cationic polymer.
A first manufacturing process comprises the steps of: preparing a solution consisting of:
at least one polyacrylonitrile bearing fixed negative charges,
at least one neutral polymer, in an amount adjusted in order to obtain the four characteristics (1)-(4) above-mentioned,
at least one solvent for the said polyacrylonitrile and for the neutral polymer,
optionally, at least one non-solvent for the polyacrylonitrile; extruding this solution in order to form a hollow fiber or a flat membrane;
simultaneously, in the case of the preparation of a hollow fiber, or after extrusion in the case of the formation of a flat membrane, solidifying the membrane obtained by a phase inversion process by partial or total contact of the extruded product with a liquid or gaseous fluid which is chemically inert with respect to the said polymers;
washing the flat membrane or the hollow fiber obtained;
optionally, treating the flat membrane or the hollow fiber with glycerol;
preparing a semi-permeable membrane from the flat membrane or assembling a bundle of hollow fibers from the hollow fiber;
mounting the flat membrane or the bundle of hollow fibers in a case and, where appropriate, fixing caps to the case;
sterilizing the medical apparatus obtained.
When the polymer is cationic, it can be combined with the semi-permeable membrane after the extrusion step for obtaining a hollow fiber or a flat membrane, according to a second process comprising the steps of:
(a) preparing a flat membrane or a hollow fiber, which has optionally been treated with glycerol, by a conventional process from a solution of polyacrylonitrile bearing negative charges;
(b) assembling, in a conventional manner, the various components of the apparatus, in particular mounting the semi-permeable membrane or a bundle of hollow fibers in a case and attaching the caps to this case;
(c) simultaneously or successively, optionally removing the glycerol from the semi-permeable membrane and preparing a solution containing the cationic polymer in dissolved form and bringing this solution into contact with the surface of the semi-permeable membrane intended to be placed in contact with blood, it being possible for step (c) to be carried out before or after step (b), the amount of cationic polymer being adjusted in order to obtain the four characteristics (1)-(4) above-mentioned,
(d) when the abovementioned step (c) has been carried out subsequent to step (b), purging the apparatus of the solution containing the cationic polymer;
(e) optionally, rinsing the semi-permeable membrane in order to remove the excess of non-bound cationic polymer and, optionally, retreating the semi-permeable membrane with glycerol;
(f) sterilizing the medical apparatus.
Advantageously, the cationic polymer is water-soluble and the solution in which this polymer is dissolved is aqueous.
In the case of a flat semi-permeable membrane, this membrane can be combined with a neutral or cationic polymer, preferably a cationic polymer, using a spraying process comprising the following steps:
(a) preparing a flat membrane, which has optionally been treated with glycerol, from a solution of polyacrylonitrile bearing negative charges;
(b) simultaneously or consecutively, optionally removing the glycerol from the semi-permeable membrane and preparing a solution containing the cationic or neutral polymer in dissolved form and spraying this solution onto the surface of the semi-permeable membrane intended to be placed in contact with blood, the amount of cationic or neutral polymer being adjusted in order to obtain the four characteristics (1)-(4) above-mentioned,;
(c) assembling the various components of the apparatus, in particular mounting the semi-permeable membrane in a case and attaching the caps to this case;
(d) optionally, rinsing the semi-permeable membrane in order to remove the excess of non-bound cationic polymer and, optionally, retreating the semi-permeable membrane with glycerol;
(f) sterilizing the medical apparatus.
In addition, in the context of the above-mentioned processes for manufacturing apparatus for the treatment of blood or plasma by extra-corporal circulation, for preventing activation of the contact phase and comprising a semi-permeable membrane in the form of a flat membrane or a bundle of hollow fibers, based on polyacrylonitrile bearing fixed negative charges and combined with a neutral or cationic polymer, the amount of polymer, whether it is neutral or cationic, is adjusted so as to satisfy the following conditions:
the overall ionic capacity of the semi-permeable membrane, based on polyacrylonitrile bearing fixed negative charges and containing a polymer (neutral or cationic), is negative;
the overall ionic capacity of the semi-permeable membrane, based on polyacrylonitrile bearing fixed negative charges and containing a polymer (neutral or cationic), is, as an absolute value, not more than 10% less than the overall ionic capacity of the same semi-permeable membrane which does not contain polymer (neutral or cationic); preferably, it is, as an absolute value, not more than 1% less than the overall ionic capacity of the same semi-permeable membrane which contains no polymer;
the electrical characteristics of the semi-permeable membrane containing a polymer (neutral or cationic) satisfies one or other of the following two conditions:
the electrokinetic index xe2x80x9cIxe2x80x9d is equal to Log10 (|Z|/R), i.e. to the logarithm, in base 10, of the ratio |Z|/R of the Zeta potential xe2x80x9cZxe2x80x9d, as an absolute value, expressed in microvolts (or xcexcV), of the surface of the membrane intended to come into contact with the blood or plasma, to the electrical resistivity xe2x80x9cRxe2x80x9d of the membrane, expressed in ohm.centimetres (or xcexa9xc2x7cm), is less than or equal to 0.8, or
the Zeta potential xe2x80x9cZxe2x80x9d is positive and is between 0 and +15 mV (limits not included).
Preferably, the electrokinetic index xe2x80x9cIxe2x80x9d is less than or equal to 0.7 and better still less than or equal to 0.6.
Preferably, when the Zeta potential is positive, it is greater than or equal to 1 mV and strictly less than 15 mV.
Other operating conditions for preparing the semi-permeable membrane may be found in U.S. Pat. No. 4,749,619 (gelation process) or in U.S. Pat. No. 4,056,467 (coagulation process).
Depending on the case, the sterilization technique which will be used, without any significant effect on the bonding between the neutral or cationic polymer and the semi-permeable membrane based on polyacrylonitrile, may be sterilization by irradiation, in particular by gamma irradiation, or sterilization with ethylene oxide.
The abovementioned processes for manufacturing apparatus for the treatment of blood or plasma by extra-corporal circulation have a major advantage: the apparatus obtained does not require any specific manipulation on the part of the user, in particular during the phases of rinsing and priming the apparatus, and the use of the apparatus by the user is entirely identical to that of any apparatus of the same type.
Lastly, the invention relates to apparatus for the treatment of blood or plasma by extra-corporal circulation, which is sterilized and ready to use, for preventing activation of the contact phase and comprising a semi-permeable membrane, in the form of a flat membrane or a bundle of hollow fibers, based on polyacrylonitrile bearing fixed negative charges, characterized in that, before or after formation of the semi-permeable membrane, and before sterilization, at least one neutral or cationic polymer is incorporated into the semi-permeable membrane, in a suitable amount such that:
the overall ionic capacity of the semi-permeable membrane, based on polyacrylonitrile bearing fixed negative charges and containing a neutral or cationic polymer, is negative;
the overall ionic capacity of the semi-permeable membrane, based on polyacrylonitrile bearing fixed negative charges and containing a neutral or cationic polymer, is, as an absolute value, not more than 10% less than the overall ionic capacity of the same semi-permeable membrane which contains no neutral or cationic polymer;
the semi-permeable membrane based on polyacrylonitrile bearing fixed negative charges and containing a neutral or cationic polymer complies with one or other of the following electrical characteristics:
the electrokinetic index xe2x80x9cIxe2x80x9d of the membrane containing a neutral or cationic polymer is less than or equal to 0.8, xe2x80x9cIxe2x80x9d being equal to the logarithm, in base 10, of the ratio |Z|/R, where xe2x80x9cZxe2x80x9d is the Zeta potential, as an absolute value, expressed in microvolts, of the surface of the membrane intended to come into contact with blood or plasma, and where xe2x80x9cRxe2x80x9d is the electrical resistivity of the membrane, expressed in ohm.centimetres, or
the Zeta potential is positive and ranges between 0 and +15 mV (limits not included).
Preferably, the electrokinetic index xe2x80x9cIxe2x80x9d is less than or equal to 0.7 and better still less than or equal to 0.6.
Preferably, when the Zeta potential is positive, it is greater than or equal to 1 mV and strictly less than 15 mV.